Identifying the mechanisms of leukemia progression

项目概要 自 2002 年以来，我的实验室在所有急性巨核细胞白血病病例中发现了 GATA1 突变。 对于患有唐氏综合症的儿童，我一直处于定义促进唐氏综合症的特定遗传事件的最前沿 白血病。我广泛研究了GATA1在正常和恶性造血中的作用并获得了许多 深入了解多个 21 号染色体基因（包括 DYRK1A、ERG 和 CHAF1B）在 白血病。我的实验室在骨髓增生性肿瘤（MPN）领域也很成熟， 特别是巨核细胞在骨髓纤维化发病机制中的作用和新的细胞的发展 针对这种疾病的治疗方法。在此 R35 申请中，我建议在未来 7 年中重点关注我的实验室（以及 超越）了解克隆性造血疾病进展为白血病的机制。 具体来说，我们将确定并比较儿科和成人疾病进展为急性髓系疾病的方式 白血病。我们将利用大规模 CRISPR/Cas9 筛选、动物模型和主要患者样本来 深入描述转型机制，重点回答三个问题：1）什么是转型机制？ 促进儿童与成人血液疾病恶性进展的相似和不同事件？ 2） 已确定的肿瘤抑制基因下游通路的失调如何促进恶性 进展？ 3) 哪些研究中或已批准的疗法可以预防肿瘤进展或治疗肿瘤？的 这些问题的答案将增加我们对癌症的基本了解，揭示新的治疗靶点并 可能有助于阐明化学预防策略。

PROJECT SUMMARY Since 2002 when my laboratory discovered GATA1 mutations in all cases acute megakaryocytic leukemia in children with Down syndrome, I have been at the forefront of defining the specific genetic events that promote leukemia. I have extensively studied the role of GATA1 in normal and malignant hematopoiesis and gained many insights into the contributions of several chromosome 21 genes, including DYRK1A, ERG and CHAF1B, in leukemia. My laboratory is also well established in the field of the myeloproliferative neoplasms (MPNs), especially in the role of megakaryocytes in the pathogenesis of myelofibrosis and the development of new therapies for this disease. In this R35 application, I propose to focus my laboratory over the next 7 years (and beyond) on understanding the mechanisms of leukemia progression from clonal hematopoietic disorders. Specifically, we will identify and compare the ways that pediatric and adult disorders progress to acute myeloid leukemia. We will leverage large scale CRISPR/Cas9 screening, animal models and primary patient samples to deeply characterize the mechanisms of transformation and focus on answering three questions: 1) What are the similar and disparate events that promote malignant progression of pediatric versus adult blood disorders? 2) How does dysregulation of pathways downstream of identified tumor suppressor genes promote malignant progression? 3) Which investigational or approved therapies can prevent progression or treat the tumors? The answers to these questions will increase our basic understanding of cancer, reveal new therapeutic targets and possibly shed light on chemoprevention strategies.